The invention relates to glucagon receptor antagonist compounds, compositions containing such compounds and various methods of treatment relating to type 2 diabetes mellitus and related conditions.
Diabetes refers to a disease process derived from multiple causative factors and is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting or postprandial state. Elevated levels of plasma glucose can result in various symptoms, including impacted (blurry) vision, excessive thirst, fatigue, hunger, frequent urination and weight loss. Left untreated, hyperglycemia can lead to serious vision problems, sores and infections in the feet and skin, nerve damage, and cardiovascular complications.
Absolute or relative elevations in glucagon levels have been shown to contribute to the hyperglycemic state in some patients with type 1 or type 2 diabetes. Glucagon is a key hormonal agent that acts in concert with insulin to mediate homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (important among these are liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Glucagon exerts its action by binding to and activating its receptor. Both in healthy control animals as well as in animal models of type 1 and type 2 diabetes, neutralization of the effect of circulating glucagon with selective and specific antibodies has resulted in reduction of the glycemic level. Mice with a homozygous deletion of the glucagon receptor exhibit increased glucose tolerance. Also, inhibition of glucagon receptor expression using antisense oligonucleotides ameliorates diabetic syndrome in db/db mice. These studies suggest that glucagon suppression or an action that antagonizes glucagon action could be a useful adjunct to conventional treatment of hyperglycemia in diabetic patients. The action of glucagon can be suppressed by providing an antagonist or an inverse agonist, e.g., substances that inhibit or prevent constitutive, or glucagon-induced, glucagon receptor-mediated responses.
Glucagon receptor antagonists have been disclosed in the art, see, e.g., WO 2008/042223. It would be useful to identify additional glucagon receptor antagonists and particularly glucagon receptor antagonists offering improved properties.